Specific immunity can be enhanced by the use of adjuvants when administering antigen to a host. The immune response is mediated by a variety of cells in the immune system. There are two types of immune response: humoral immunity mediated by antibodies, and cellular immunity mediated primarily by cytotoxic T lymphocytes. Antigen presenting cells ("APC") process and present antigen to both B and T cells. B cells secrete specific antibodies as a result of activation and T cells either become helper cells to the humoral response or cytotoxic cells and directly attack the antigen. Adjuvants have been shown to augment these immune responses.
Initial presentation of an antigen induces both IgM and IgG antibodies, forming the primary response. This production of antibodies may fall off, however, over time. A secondary response, which principally involves the production of IgG antibodies, may be triggered by the secondary or later in time presentation of the antigen. A secondary or even primary response, however, is not guaranteed merely by priming the host with an antigen.
A difficulty often encountered in the administration of an antigen is the extent the immune system will respond. Certain antigens are not very immunogenic in that upon administration they provoke a weak primary response or no response at all. In such cases, the immune system may not respond to a secondary challenge, and for example, the host may suffer from the disease or condition that the immunization with the antigen was designed to prevent.
In such situations, it is common to give a biological response modifier ("BRM"). A BRM generally is defined as an immunopotentiating compound. It may be derived from bacteria, such as Bordella pertussis or Corynebacterium parvum. BRM also may include chemicals, such as polynucleotides, physiologically active molecules, such as thymic hormones, and adjuvants.
Adjuvants are compounds which enhance the immune systems response when administered with antigen producing higher antibody titres and prolonged host response. Commonly used adjuvants include Incomplete Freund's Adjuvant, which consists of a water in oil emulsion, Freund's Complete Adjuvant, which comprises the above with the addition of Mycobacterium tuberculosis, and alum. The difficulty, however, in using these materials in humans, for example, is that they are toxic or may cause the host to develop lesions at the site of injection.
This problem was recognized in EPA 87304005.9, published Nov. 11, 1987 ("Barber Application"). In the Barber Application, they sought to avoid the problem by coupling the antigen to a monoclonal antibody which was specific for a surface structure on "antigen presenting cells." APC generally consist of B cells and macrophages (but exclude T cells). Specifically, monoclonal antibodies directed against Class I and Class II cell surface MHC glycoproteins were described. These antibodies included anti-I-A and anti-I-E which were coupled to a variety of antigenic materials, including avidin, bovine serum albumin and strepavidin. The results suggested that antigens coupled to anti-Class I or Class II antibodies would provide a greater immune response than if the antigens had been presented without having been conjugated to the anti-Class I and anti-Class II antibodies. There was no suggestion that antibodies directed against non-MHC restricted structures might be used as adjuvants. Surprisingly, antibodies against cell surface structures other than those associated with Class I and Class II glycoproteins provide an enhanced immune response greater than that disclosed in the Barber Application.
Another approach was described by Kawamura and Berzofsky in J. Immunol., 136:58 (1986). In this approach, anti-Ig antibodies, which are reactive with immunoglobulins present on certain B cells, were conjugated to ferritin and myoglobin, and were administered to mice with Incomplete Freund's Adjuvant. Immunogenicity of the mixture was improved, but there was no indication of the immunogenicity of the mixture without the addition of the adjuvant.